The present invention relates to a new use, in particular a new pharmaceutical use for compounds having 5-HT3 (serotonin M) receptor, in particular specific 5-HT3 receptor, antagonist activity, especially in the manufacture of a pharmaceutical composition.
Specifically, the present invention relates to the treatments defined below.
The 5-HT3-receptor antagonists comprise a defined and recognised class of pharmaceutically active compounds well known in the art and characterised, as their name implies, by their pharmacological activity. Various 5-HT3 receptor antagonist compounds are commercially available and clinically applied, e.g. in the treatment of emesis.
In accordance with the present invention it has now surprisingly been found that 5-HT3 receptor antagonists are useful for the treatment of local non-inflammatory, local irritation-related and local inflammatory disease conditions. This is surprising in that (a) the 5-HT3 receptor antagonists are effective alone; (b) do not only bring pain relief, but also are effective in the treatment of other symptoms, such as effusion, swelling, stiffness and the like, and (c) are locally effective, thus not having to rely on systemic administration that may show effects e.g. by working via effects on nerves and/or synapses at the spinal cord. It is also astonishing that relatively high local doses are both tolerated and effective when local administration is employed.
Hence, the present invention relates to the use of a 5-HT3 receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present for example the treatment of any process, condition, event, or disease as hereinafter described. In particular, the present invention provides the use as mentioned before where, in addition to pain at least one further sequela or symptom of the local disease, local irritation condition or local manifestation is alleviated, ameliorated or controlled.
Any 5-HT3 receptor antagonist can be used in accordance with the invention. Preferred 5-HT3 receptor antagonists which may be employed in accordance with the present invention are:
A) Ondansetron [1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl]methyl]-4H-carbazol-4-one (cf. Merck Index, twelfth edition, item 6979);
B) Granisetron [endo-1-methyl-N-(9-methyl-9-aza-bicyclo[3.3.1]non-3-yl)-1H-imidazole-3-carboxamide: (cf. loc. cit., item 4557); and
C) Dolasetron [1H-indole-3-carboxylic acid (2xcex1, 6xcex1, 8xcex1, 9xcex1xcex2)-octahydro-3-oxo-2,6methano-2H-quinolizin-8-yl ester] (cf. loc. cit., item 3471).
Particular 5-HT3 receptor antagonists which may be employed in accordance with the present invention are those of the formula 1 as defined in European Patent Publication 189002 B1, the contents of which are incorporated herein by reference, in particular the compound:
D) Indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo[3,2,1]-oct-3-yl-ester, also known as tropisetron. (cf. loc.cit., item 9914).
Further 5-HT3 receptor antagonists which may be used preferably in accordance with the present invention are:
E) 4,5,6,7-tetrahydro-5-[(1-methyl-indol-3-yl)carbonyl]benzimidazole (see also ramosetron, see U.S. Pat. No. 5,344,927);
F) (+)-10-methyl-7-(5-methyl-1H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-6-one (see also fabesetron, EP 0 361 317); and
G) [N-(1-ethyl-2-imidazolin-2-yl-methyl)-2-methoxy-4-amino-5-chlorobenzamide (see also lintopride-Chem.-Abstr.-No. 107429-63-0).
A further 5-HT3 receptor antagonists which may be used preferably in accordance with the present invention is
(H) 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (see also alosetron, EP 0 306 323).
5-HT3-receptor antagonists may be employed in accordance with the invention in free or in pharmaceutically acceptable salt form, e.g. as known in the art, for example, in the case of compounds A) to D) above in pharmaceutically acceptable acid addition salt form, for example, in the case of: compound A) the hydrochloride dihydrate; compound B) the hydrochloride; compound C) the mesylate; and compound D) the monohydrochloride. References to 5-HT3 receptor antagonists collectively or individually throughout the present specification and claims are accordingly to be understood as embracing both free compounds and such pharmaceutically acceptable salt forms, e.g. as clinically employed, and further also solvates, e.g. hydrates, or specific crystal forms of any of these compounds or salts.
For use in accordance with the present invention tropisetron (especially in the formulation called NAVOBAN(copyright)) is most preferred.
Thus, the invention relates to the use of a 5-HT3 receptor antagonist or of a pharmaceutically acceptable salt of such an antagonist for the manufacture of a pharmaceutical composition for the treatment of a non-inflammatory local disease of the musculo-sceletal system, of a local irritation condition of a joint or tendon sheath, or for the local treatment a local manifestation at the locomotor apparatus of an inflammatory disease except for a crystal induced arthritis and a living pathogen induced inflammatory disease condition as long as the living pathogen is still present, where the 5-HT3 receptor antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, tropisetron, ramosetron, fabesetron, lintopride and alosetron, which may be used in free form or as a pharmaceutically acceptable salt.
In accordance with the present invention it has now surprisingly been found that 5-HT3 receptor antagonists are useful for the treatment of certain diseases, processes, conditions or events, namely non-inflammatory local diseases of the musculo-sceletal system; local irritation conditions of the joints or tendon sheaths; or the local treatment also of local manifestations at the locomotor apparatus of inflammatory diseases; such as conditions, processes or events that are due to trauma (including surgery or preferably accident); overload; posture fault; degenerative processes; conditions subsequent to another disease (including infection, for example viral infection, or tumor diseases); or other conditions that result in irritation of the locomotor apparatus of the body; meaning especially therapy of the respective non-inflammatory disease, irritation or manifestation as such, its sequelae or its symptoms, or any combinations of these.
xe2x80x9cTreatmentxe2x80x9d as used herein includes use for the alleviation, amelioration or control of said diseases, processes, conditions or events. It also includes intervention for the alleviation, amelioration or control of the sequelae or symptoms of any one or more of these diseases, for example degeneration (e.g. of cells, epithelia or tissues), swelling, exudation, effusion or pain, stiffness or inflexibility of joints. In this context the term xe2x80x9ctreatmentxe2x80x9d is further to be understood as embracing use to reverse, restrict or control progression of any specified disease, process, condition event or the like, including use for disease modifying effect. If any of the mentioned diseases, processes, conditions, manifestations or events, especially an inflammatory disease, process, condition, manifestation or event, is associated with pain, the term xe2x80x9ctreatmentxe2x80x9d preferably encompasses the alleviation, amelioration or control (including temporal or permanent removal) of at least one further sequela or symptom in addition to pain, such as swelling, effusion, exsudation, lack of flexibility (e.g. due to stiffness and/or lack of flexibility of joints), loss of strength or degeneration, more preferably of all symptoms and most preferably of the total clinical picture of the respective disease, irritation or manifestation. According to the present invention, the term xe2x80x9ctreatmentxe2x80x9d preferably does not have the meaning of prevention.
The present invention is in particular applicable to the treatment of:
(1) non-inflammatory local diseases of the musculo-sceletal system (including a joint or another part of the locomotor apparatus), such as
(1a) myofasciale syndrome, including myelogelosis, chronic lumbalgia or cervicalgia, for example unspecific or in the context of degenerative spinal affections, of static posture fault or malformation of the spine, e.g. cervical syndrome,
(1b) tendomyosis, tendinosis, insertion tendopathy (e.g. epicondylitis), bursopathy or peri-arthropathy,
(1c) overload syndrome of the muscle,
(1d) syndromes due to the compression of nerves or neuropathy (such as medianus compression syndrome=carpal tunnel syndrome), or
(1e) algodystrophy (also called neurodystrophy); or
(2) local irritation conditions (=states of irritation) of a joint or tendon sheath especially related to
(2a) a meniscus lesion (e.g. following surgical intervention or preferably due to damage to the meniscus due to a different cause),
(2b) arthrosis, such as gonarthrosis,
(2c) trauma, including accident or post-operative trauma, e.g. after implant or insertion surgery or endoscopy,
(2d) osteochondritis dissecans, osteonecrosis or joint chondromatosis,
(2e) or various non-inflammatory rheumatoid diseases, preferably to the local treatment of one or more of the mentioned diseases under (1) and/or (2); or
(3) to the local treatment also of a local manifestation at the locomotor apparatus of an inflammatory disease, such as various inflammatory rheumatoid diseases (except for crystal induced arthritis (e.g. gout) and except for living pathogen induced diseases as long as the living pathogen (bacterium, virus or fungus, protozoon, parasite or the like) is still present), such as
(3a) chronic polyarthritis (=rheumatoid arthritis), including juvenile arthritis or psoriasis arthropathy;
(3b) sarcoidosis,
(3c) paraneoplastic syndrome or tumor-induced inflammatory diseases,
(3d) turbid effusions,
(3e) collagenosis, such as systemic Lupus erythematosus, poly-myositis, dermato-myositis, systemic sclerodermia or mixed collagenosis;
(3f) postinfectious arthritis (where no living pathogenic organism can be found at or in the affected part of the body), or
(3g) seronegative spondylarthritis, such as spondylitis ankylosans; or further
(3h) vasculitis.
In the case of the inflammatory diseases, diseases where a living pathogen, e.g. a virus, a bacterium, a fungus, a protozoon or a parasite or the like, is still present, the treatment of must first aim at removal of the pathogen causative for the disease, before treatment with a 5-HT3 antagonist is used, as otherwise there is the danger that the causative pathogen remains intact. Then the mere symptomatic treatment with a 5-HT3 antagonist is contraindicated in order to avoid survival or even further spread of the causative infection. This is also valid in the case of combination with an anti-inflammatory glucocorticosteroid as described in the following, as is the proviso that treatment of crystal-induced inflammation is excluded.
The term xe2x80x9clocomotor apparatusxe2x80x9d refers to any component of the musculo-sceletal system of the body, especially to bony tissue, muscle, tendons, ligaments, joints, cartilage, perichondrium, periosteum, synovial membrane, bursa and the like.
xe2x80x9cTraumaxe2x80x9d refers preferably to operative and more preferably to trauma by accident, such as overload, tumble or push.
The term xe2x80x9clocal treatmentxe2x80x9d refers to the treatment with one or more 5-HT3 receptor antagonists near or at the site of the manifestation of the disease to be treated, e.g. by intra-muscular injection, intra-articular injection, or any other injection near or at the site of disease manifestation (that is, preferably the administration has the goal to provide for locally higher concentrations of the administered compound than would be expected to be achieved by systemic administration, or the goal is not systemic exposure), preferably within an area within 20, more preferably 10 cm, still more preferably within 5 cm, around the outer limitation of the manifestation of the local disease, most preferably directly at the affected are or site, e.g. the are or site of symptom manifestation, such as the area of greatest pain, such as an insertion point, a trigger point or a joint, or also in a broader aspect of the invention by local tissue infiltration or transdermal administration at the site of the manifestation of the disease, e.g. by means of topical administration e.g. by use of gels, creams or ointments or the like, or by transdermal patch technology. In the case of the non-inflammatory diseases mentioned above under (1) and (2), also systemic treatment is possible, e.g. by enteral, especially peroral, e.g. by use of tables or capsules, or rectal, e.g. by use of enemation or suppositories; subcutaneous, intraperitoneal or intra-muscular injection; or infusion is possible. In the case of intravenous administration bolus injection is preferred. However, local treatment is preferred in all cases. An advantage of local treatment is that high efficiency can be reached and that systemic exposure to a 5-HT3 antagonist can be diminished or avoided. One preferred local way of administration is the intra-articular injection in case of diseases, conditions etc. that relate to joints, e.g. bursopathy or synovitis.
A preferred example of a local manifestation at the locomotor apparatus of an inflammatory disease is synovial inflammation, for example, synovitis, including any of the particular forms of synovitis recited in Dorland""s Illustrated Medical Dictionary, 26th edition, pub. W. B. Saunders and Co. at page 1301, as far as it is not crystal-induced. Such synovial inflammation may for example, be consequential to or associated with disease, e.g. arthrosis, including arthritis, e.g. osteoarthritis, rheumatoid arthritis or arthritis deformans.
Further preferred local diseases to be treated according to the invention are those mentioned in the examples.
From the foregoing it will be noticed that the present invention is to be understood especially as embracing the treatment, e.g. therapy, of any disease, process, symptom, event or condition as set forth above, for example for the alleviation or control of non-inflammatory local diseases or irritations or local inflammatory processes or events and the sequelae associated therewith or consequential thereto, e.g. to alleviate or control joint irritation or effusion; with the proviso that if pain is treated, then in addition at least one other disease manifestation (e.g. effusion, swelling, exudation or degeneration) is treated.
Preferably the present invention relates to the treatment, especially the local treatment, of a disease as mentioned above under (2) or (3), more preferably one of the diseases mentioned there other than algodystrophy and vasculitis.
In a further aspect it has been found in accordance with the present invention that 5-HT3 receptor antagonists are useful as replacement therapy for local glucocorticosteroid, e.g. cortisone or the like, therapy; for example for use in any means of treatment as hereinbefore and hereinafter set forth, e.g. the diseases mentioned under (2) and (3) hereinabove.
The term xe2x80x9creplacement therapyxe2x80x9d as used herein is to be understood as embracing both use xe2x80x9cas full replacementxe2x80x9d, i.e. use instead of glucocorticosteroid therapy, as well as use xe2x80x9cas partial replacementxe2x80x9d for glucocorticosteroid therapy, i.e. for administration together with glucocorticosteroid therapy or as a means of reducing glucocorticosteroid dosage or to achieve a glucocorticosteroid sparing effect.
The present invention accordingly provides:
I. A method of treating any process, condition, event, or disease as hereinbefore set forth, in a subject in need thereof, which method comprises locally administering an effective amount of a 5-HT3 receptor antagonist, especially locally at or near the site of the local disease, local irritation condition or local manifestation;
II. A method of providing replacement therapy for glucocorticosteroid therapy in a subject receiving such glucocorticosteroid therapy for or in the treatment of any process, condition, event or disease as hereinbefore set forth, which process comprises locally administering to said subject an effective amount, e.g. a glucocorticosteroid sparing amount, of a 5-HT3-receptor antagonist; as well as
III. A method of treating any process, condition, event or disease as hereinbefore set forth, in a subject in need thereof, which method comprises locally administering an effective amount of a 5-HT3 receptor antagonist together with a glucocorticosteroid.
Where the term xe2x80x9cglucosteroidxe2x80x9d is used, this means an anti-inflammatory glucosteroid.
Where co-administration is practiced as under III above the drug substances, i.e. 5-HT3 receptor antagonist and glucocorticosteroid may be administered sequentially or simultaneously or substantially simultaneously, e.g. employing a fixed combination dosage form.
In further aspects the present invention also provides:
IV. A 5-HT3 receptor antagonist for use in, or for use in the manufacture of a pharmaceutical composition for use in; or the use of a pharmaceutical composition comprising a 5-HT3 receptor antagonist for local use:
a) in the treatment of any process, condition, event or disease as hereinbefore set forth;
b) as replacement therapy for glucocorticosteroid therapy in the treatment of any process, condition, event or disease as hereinbefore set forth; or
c) for co-administration together with a glucocorticosteroid in the treatment of any process, condition, event or disease as hereinbefore set forth; and/or:
V. A pharmaceutical dosage form comprising a 5-HT3 receptor antagonist together with a glucocorticosteroid, especially for the local treatment of any process, condition, event or disease as hereinbefore set forth.
Where under (I) to (V) the term xe2x80x9cany process, condition, event or diseasexe2x80x9d is used, this term preferably relates to the diseases mentioned under (1), (2) and (3) above, especially as defined above as being preferred.
The term xe2x80x9clocally administeringxe2x80x9d or xe2x80x9clocal usexe2x80x9d is defined to mean local administration or especially xe2x80x9clocal treatmentxe2x80x9d as defined above, that is, administration at or near the site of the non-inflammatory disease, irritation condition or local inflammatory disease condition, in contrast to systemic administration.
Dosage forms, e.g. in accordance with V above, are to be understood as including both fixed-unit-dosage forms, e.g. liquid formulations, comprising both active ingredients together with appropriate pharmaceutically acceptable diluents or carriers, as well as twin delivery systems, packages or the like comprising both active ingredients separately or in separate dosage form, for concommitant or sequential administration.
The 5-HT3 receptor antagonists are preferably used in well-known liquid formulations.
Utility of 5-HT3 receptor antagonists in accordance with the present invention can be demonstrated in clinical trials carried out in accordance with standard techniques and methodologies, for example as follows:
The following examples are for illustrative purposes and are not intended to diminish the scope of the present invention. Instead of tropisetron, any other 5-HT3-antagonist, or a pharmaceutically acceptable salt thereof, solvate, e.g. hydrate, or crystalline form thereof, especially selected from the group consisting of ondansetron, granisetron, dolasetron, ramosetron, fabesetron, lintopride and alosetron, can be used, or any combination of two or more of these 5-HT3 receptor antagonists or pharmaceutically acceptable salts thereof.
In the following examples, tropisetron is administered in the standard formulation of the trademark Navoban(copyright) which is available in ampoules that contain 2 mg or 5 mg of the active substance, tropisetron.